Melanoma is one of the few cancers, both early and late stages that has increased in incidence over the last few decades. The poor survival of patients with advanced or metastatic melanoma reflects its aggressive nature and the ineffectiveness of current treatment and prevention strategies. Chemoprevention represents a rational alternative to combat this deadly cancer by preventing, delaying or reversing the malignant transformation of a melanocyte. Demonstrating efficacy of any preventive intervention requires long-term, randomized clinical trials involving large populations. Such studies are logistically and financially difficult to perform with a tremendous investment of time and resources. The central hypotheses of this proposal are that a human model for melanoma Chemoprevention studying patients with dysplastic nevi can be used to test putative Chemoprevention agents by modulating important molecular events and that topical curcumin can delay or prevent transformation and progression of melanocytes in humans at least in part by its modulating effects on nuclear factor kappa B (NF-kB) and 12-lipoxygenase (12-LOX). In order to test these hypotheses the following four specific aims are proposed: (1) determine the proportion of patients with dysplastic nevi in the University of Michigan Multidisciplinary Melanoma Clinic who will participate in a prospective clinical trial requiring serial skin biopsies;(2) define the intra- and inter-lesional histopathologic and biomarker variability of nuclear factor kappa B (NF-kB) activation, 12-lipoxygenase (12-LOX), and prostaglandin E2 (PGE2) expression in normal skin, benign nevi, and dysplastic nevi;(3) define the absorption, safety, tolerability, and optimal dose concentration of topical curcumin;and (4) determine if topical curcumin can significantly alter the expression of nuclear factor kappa B (NF-kB) activation, 12- lipoxygenase (12-LOX), and downstream markers (Ki-67) in pigmented skin cells. The proposed studies will demonstrate that we can recruit sufficient patients for putative chemopreventive agents, that topical curcumin is safe and tolerable, and that curcumin modulates 12-LOX expression and NF-kB release in human skin. This line of investigation will help determine the importance of NF-kB and 12-LOX in melanoma carcinogenesis and provide an infrastructure for rapid testing of putative Chemoprevention agents and biomarkers in the future.